Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) is associated with a number of human cancers in particular AIDS associated Kaposi sarcoma (KS) and pleural effusion lymphomas (PELs). KS of the soft palate as well as major involvement of the body and extremities has been known to be a common symptom associated with the onset of AIDS in the HIV immunocompromised population. This has become a pandemic and KS as well as pleural effusion lymphomas are now included as the leading causes of death in the HIV population in developing countries. KSHV was identified 15 years ago and has been tackled mostly on a level of the individual investigator. The focus of this application is to bring together 3 prominent groups of investigators within the University of Pennsylvania community to join their scientific expertise to address the mechanism of KSHV mediated oncogenesis. The overall goal will be to investigate the mechanism of viral control by encoded antigens during the early stages of infection of primary B cells. The fundamental cellular processes targeted during these early stages will provide novel new information as to the strict requirements for successful establishment of latency by the virus. The program consists of three scientific projects, an administrative core, a recombineering virus and vector core and a ChIP sequencing core. The scientific projects are: 1. The Role of the RBPJk-LANA complex during early infection; 2. KSHV abortive replication following de novo infection; 3. Chromatin regulation of KSHV during early infection of primary B-cells. The success of these projects will allow for the establishment of a more comprehensive mechanistic view of KSHV infection and pathogenesis and provide new clues for the development of strategies to prevent and treat KSHV associated cancers in the HIV population. In addition the accumulation of new information on KSHV biology will be critical for the broader area of herpesvirus biology with insights into the mechanism of oncogenesis associated with other viruses including EBV and so reducing the burden of disease in the HIV infected, transplants and other immunocompromised population